JP2013508293A5 - - Google Patents
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- JP2013508293A5 JP2013508293A5 JP2012534373A JP2012534373A JP2013508293A5 JP 2013508293 A5 JP2013508293 A5 JP 2013508293A5 JP 2012534373 A JP2012534373 A JP 2012534373A JP 2012534373 A JP2012534373 A JP 2012534373A JP 2013508293 A5 JP2013508293 A5 JP 2013508293A5
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- eniluracil
- dpd inhibitor
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- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 160
- 239000000651 prodrug Substances 0.000 claims description 83
- 229940002612 prodrugs Drugs 0.000 claims description 83
- 101700035151 preA Proteins 0.000 claims description 81
- 239000003112 inhibitor Substances 0.000 claims description 72
- 230000002401 inhibitory effect Effects 0.000 claims description 72
- 239000000203 mixture Substances 0.000 claims description 54
- JOZGNYDSEBIJDH-UHFFFAOYSA-N 5-ethynyl-1H-pyrimidine-2,4-dione Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 claims description 51
- 229950010213 Eniluracil Drugs 0.000 claims description 51
- 239000002246 antineoplastic agent Substances 0.000 claims description 38
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 23
- 229960004117 Capecitabine Drugs 0.000 claims description 19
- 230000037217 Elimination half-life Effects 0.000 claims description 12
- 230000001537 neural Effects 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 10
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 claims description 8
- 210000001519 tissues Anatomy 0.000 claims description 8
- -1 5'-deoxy-4 ' Chemical compound 0.000 claims description 7
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 6
- 230000002459 sustained Effects 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 5
- IDYKCXHJJGMAEV-RRKCRQDMSA-N 4-amino-5-fluoro-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1O[C@H](CO)[C@@H](O)C1 IDYKCXHJJGMAEV-RRKCRQDMSA-N 0.000 claims description 4
- STRZQWQNZQMHQR-UAKXSSHOSA-N 5-fluorocytidine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 STRZQWQNZQMHQR-UAKXSSHOSA-N 0.000 claims description 4
- FBOIBTWYSVRYTJ-VBLCRABPSA-N FC1[C@H]([C@H]([C@@H](C(O1)C=1C(NC(NC=1)=O)=O)O)O)O Chemical compound FC1[C@H]([C@H]([C@@H](C(O1)C=1C(NC(NC=1)=O)=O)O)O)O FBOIBTWYSVRYTJ-VBLCRABPSA-N 0.000 claims description 4
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N Floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 4
- 206010029350 Neurotoxicity Diseases 0.000 claims description 4
- 206010044221 Toxic encephalopathy Diseases 0.000 claims description 4
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 claims description 4
- 230000002887 neurotoxic Effects 0.000 claims description 4
- 231100000228 neurotoxicity Toxicity 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Natural products O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 229940035893 Uracil Drugs 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- BLXGZIDBSXVMLU-OWOJBTEDSA-N 5-[(E)-2-bromoethenyl]-1H-pyrimidine-2,4-dione Chemical compound Br\C=C\C1=CNC(=O)NC1=O BLXGZIDBSXVMLU-OWOJBTEDSA-N 0.000 description 2
- UJBCLAXPPIDQEE-UHFFFAOYSA-N 5-prop-1-ynyl-1H-pyrimidine-2,4-dione Chemical compound CC#CC1=CNC(=O)NC1=O UJBCLAXPPIDQEE-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- HAUXRJCZDHHADG-UHFFFAOYSA-N 2,4-dioxo-1H-pyrimidine-5-carbonitrile Chemical compound O=C1NC=C(C#N)C(=O)N1 HAUXRJCZDHHADG-UHFFFAOYSA-N 0.000 description 1
- CYMBDTMRFAUHRM-UHFFFAOYSA-N 5-(1-chloroethenyl)-1H-pyrimidine-2,4-dione Chemical compound ClC(=C)C1=CNC(=O)NC1=O CYMBDTMRFAUHRM-UHFFFAOYSA-N 0.000 description 1
- LKTQRCSUYNIRSM-UHFFFAOYSA-N 5-(2-bromoethynyl)-1H-pyrimidine-2,4-dione Chemical compound BrC#CC1=CNC(=O)NC1=O LKTQRCSUYNIRSM-UHFFFAOYSA-N 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-Bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 1
- ZRYZBEQILKESAW-UHFFFAOYSA-N 5-ethenyl-1H-pyrimidine-2,4-dione Chemical compound C=CC1=CNC(=O)NC1=O ZRYZBEQILKESAW-UHFFFAOYSA-N 0.000 description 1
- TUFMBCUUDJKPJB-UHFFFAOYSA-N 5-hex-1-ynyl-1H-pyrimidine-2,4-dione Chemical compound CCCCC#CC1=CNC(=O)NC1=O TUFMBCUUDJKPJB-UHFFFAOYSA-N 0.000 description 1
- KSNXJLQDQOIRIP-UHFFFAOYSA-N 5-iodouracil Chemical compound IC1=CNC(=O)NC1=O KSNXJLQDQOIRIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
Description
本発明の別の一態様によれば、ＤＰＤ阻害剤及び５−ＦＵ又は５−ＦＵプロドラッグを含む徐放性経口医薬製剤であって、製剤を患者に投与した後、５−ＦＵ又は５−ＦＵプロドラッグは、ＤＰＤ阻害剤が放出された後少なくとも約１１〜１６時間まで実質的に放出されず、その放出後に５−ＦＵ又はプロドラッグから生成される５−ＦＵが、患者に残留するＤＰＤ阻害剤の少なくとも約１０倍過剰で患者中に存在する、徐放性経口医薬製剤が提供される。
本発明は、例えば以下の項目を提供する。
（項目１）
ＤＰＤ阻害剤及び５−ＦＵ又は５−ＦＵプロドラッグから選択される抗癌剤を含む組合せを用いて、癌患者の処置に付随する神経毒性を最小限にする方法であって、
神経組織と非神経組織の両方におけるＤＰＤ活性を実質的に消失させるのに十分な用量でＤＰＤ阻害剤をまず投与する工程、及び
その後に前記５−ＦＵ又は５−ＦＵプロドラッグを投与する工程
を含み、前記５−ＦＵ又は５−ＦＵプロドラッグが、前記５−ＦＵ又は前記５−ＦＵプロドラッグから生成される５−ＦＵが前記ＤＰＤ阻害剤よりもかなり過剰に前記患者中に存在するような用量で投与される、方法。
（項目２）
前記ＤＰＤ阻害剤が約１６〜４０ｍｇ／ｍ ２ の用量で投与される、項目１に記載の方法。
（項目３）
前記ＤＰＤ阻害剤が約１６〜２５ｍｇ／ｍ ２ の用量で投与される、項目１に記載の方法。
（項目４）
前記５−ＦＵ又は５−ＦＵプロドラッグが、前記ＤＰＤ阻害剤が投与されてから約１１〜１６時間後に投与される、項目１に記載の方法。
（項目５）
前記５−ＦＵ又は５−ＦＵプロドラッグが、前記ＤＰＤ阻害剤が投与されてから前記ＤＰＤ阻害剤の少なくとも約３〜５排出半減期が経過したときに投与される、項目１に記載の方法。
（項目６）
前記ＤＰＤ阻害剤が、前記患者における神経及び非神経組織において、ＤＰＤ活性を前記患者におけるベースラインＤＰＤ活性の５％未満に低下させるのに十分な用量で投与される、項目１に記載の方法。
（項目７）
前記５−ＦＵ又は５−ＦＵプロドラッグが、その投与時において前記５−ＦＵ又はプロドラッグから生成される５−ＦＵが前記ＤＰＤ阻害剤の少なくとも１０倍過剰で前記患者中に存在するような用量で投与される、項目１に記載の方法。
（項目８）
前記５−ＦＵプロドラッグが、５−フルオロウリジン、５−フルオロシチジン、５−フルオロ−２−デオキシウリジン、５−フルオロ−２−デオキシシチジン、５’−デオキシ−４’，５−フルオロウリジン、及び５−フルオロアラビノシルウラシル、５’−デオキシ−５−フルオロウリジン、１−（２−テトラヒドロフラニル）−５−フルオロウラシル、１−Ｃ １〜８ アルキルカルバモイル−５−フルオロウラシル誘導体、１−（２−テトラヒドロフリル）−５−フルオロウラシル、５’−デオキシ−５−フルオロ−Ｎ−［（ペンチルオキシ）カルボニル］−シチジン（カペシタビン）、又は５−ＦＵにｉｎ ｖｉｖｏで変換される化合物からなる群、及びリン酸エステルを含めたその５’−エステルから選択される、項目１に記載の方法。
（項目９）
前記抗癌剤が５−ＦＵである、項目１に記載の方法。
（項目１０）
前記抗癌剤がカペシタビンである、項目１に記載の方法。
（項目１１）
前記ＤＰＤ阻害剤が５−置換ウラシル化合物又はそのプロドラッグを含む、項目１に記載の方法。
（項目１２）
前記ＤＰＤ阻害剤が、ハロゲン原子、Ｃ ２〜４ アルケニル基、ハロゲンで置換されたＣ ２〜４ アルケニル基、Ｃ ２〜６ アルキニル基、ハロゲンで置換されたＣ ２〜６ アルキニル基、シアノ基、Ｃ １〜４ アルキル基、又はハロゲンで置換されたＣ １〜４ アルキル基で、５位が置換されたウラシル化合物を含む、項目１に記載の方法。
（項目１３）
前記ＤＰＤ阻害剤が、エニルウラシル、５−プロパ−１−イニルウラシル、５−シアノウラシル、５−プロパ−１−イニルウラシル、５−ブロモエチニルウラシル、５−（１−クロロビニル）ウラシル、５−ヨードウラシル、５−（２−ブロモビニル）ウラシル、（Ｅ）−５−（２−ブロモビニル）ウラシル、５−ヘキサ−１−イニルウラシル、５−ビニルウラシル、５−トリフルオロウラシル、５−ブロモウラシル及び５−（２−ブロモ−１−クロロビニル）ウラシルからなる群から選択されるウラシル化合物を含む、項目１に記載の方法。
（項目１４）
前記ＤＰＤ阻害剤がエニルウラシル又はそのプロドラッグである、項目１に記載の方法。
（項目１５）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤が５−ＦＵである、項目１に記載の方法。
（項目１６）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤がカペシタビンである、項目１に記載の方法。
（項目１７）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤が５−ＦＵであり、前記エニルウラシルが約１６〜４０ｍｇ／ｍ ２ の用量で投与され、前記５−ＦＵがその約１１〜１６時間後に約１５〜５０ｍｇ／ｍ ２ の用量で投与される、項目１に記載の方法。
（項目１８）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤が５−ＦＵプロドラッグであり、前記エニルウラシルが約１６〜４０ｍｇ／ｍ ２ の用量で投与され、前記５−ＦＵプロドラッグがその約１１〜１６時間後に約４０〜１５０ｍｇ／ｍ ２ の用量で投与される、項目１に記載の方法。
（項目１９）
前記５−ＦＵプロドラッグがカペシタビンである、項目１８に記載の方法。
（項目２０）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤が５−ＦＵであり、前記エニルウラシルが約１６〜４０ｍｇ／ｍ ２ の用量で投与され、前記エニルウラシルが投与されてから前記エニルウラシルの少なくとも約３〜５排出半減期が経過したときに前記５−ＦＵが約１５〜５０ｍｇ／ｍ ２ の用量で投与される、項目１に記載の方法。
（項目２１）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤が５−ＦＵプロドラッグであり、前記エニルウラシルが約１６〜４０ｍｇ／ｍ ２ の用量で投与され、前記エニルウラシルが投与されてから前記エニルウラシルの少なくとも約３〜５排出半減期が経過したときに前記５−ＦＵプロドラッグが約４０〜１５０ｍｇ／ｍ ２ の用量で投与される、項目１に記載の方法。
（項目２２）
前記５−ＦＵプロドラッグがカペシタビンである、項目２１に記載の方法。
（項目２３）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤が５−ＦＵであり、前記エニルウラシルが前記患者における神経及び非神経組織においてＤＰＤ活性を前記患者におけるベースラインＤＰＤ活性の５％未満に低下させるのに十分な用量で投与され、前記５−ＦＵがその約１１〜１６時間後に約１５〜５０ｍｇ／ｍ ２ の用量で投与される、項目１に記載の方法。
（項目２４）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤が５−ＦＵプロドラッグであり、前記エニルウラシルが前記患者における神経及び非神経組織においてＤＰＤ活性を前記患者におけるベースラインＤＰＤ活性の５％未満に低下させるのに十分な用量で投与され、前記５−ＦＵプロドラッグがその約１１〜１６時間後に約４０〜１５０ｍｇ／ｍ ２ の用量で投与される、項目１に記載の方法。
（項目２５）
前記５−ＦＵプロドラッグがカペシタビンである、項目２４に記載の方法。
（項目２６）
前記ＤＰＤ阻害剤がエニルウラシルであり、前記抗癌剤が５−ＦＵ又は５−ＦＵプロドラッグであり、前記エニルウラシルが約１６〜４０ｍｇ／ｍ ２ の用量で投与され、前記５−ＦＵ又は５−ＦＵプロドラッグがその約１１〜１６時間後に、前記５−ＦＵ又は前記５−ＦＵプロドラッグから生成される５−ＦＵが前記ＤＰＤ阻害剤の少なくとも１０倍過剰で前記患者中に存在するような用量で投与される、項目１に記載の方法。
（項目２７）
ＤＰＤ阻害剤及び５−ＦＵ又は５−ＦＵプロドラッグを含む徐放性経口医薬製剤であって、前記製剤を患者に投与後、前記ＤＰＤ阻害剤が放出された後少なくとも約１１〜１６時間まで前記５−ＦＵ又は５−ＦＵプロドラッグが実質的に放出されず、その放出後に前記５−ＦＵ又はプロドラッグから生成される５−ＦＵが、前記患者に残留する前記ＤＰＤ阻害剤の少なくとも約１０倍過剰で前記患者中に存在する、徐放性経口医薬製剤。
According to another aspect of the invention, a sustained release oral pharmaceutical formulation comprising a DPD inhibitor and a 5-FU or 5-FU prodrug, wherein the formulation is administered to a patient, and then 5-FU or 5- The FU prodrug is not substantially released until at least about 11-16 hours after the DPD inhibitor is released, and 5-FU or 5-FU produced from the prodrug remains in the patient after the release. Sustained release oral pharmaceutical formulations are provided that are present in a patient in at least about a 10-fold excess of the inhibitor.
For example, the present invention provides the following items.
(Item 1)
A method of minimizing neurotoxicity associated with the treatment of cancer patients using a combination comprising a DPD inhibitor and an anti-cancer agent selected from 5-FU or 5-FU prodrugs comprising:
First administering a DPD inhibitor at a dose sufficient to substantially eliminate DPD activity in both neural and non-neural tissues; and
And then administering the 5-FU or 5-FU prodrug
The 5-FU or 5-FU prodrug is such that the 5-FU or 5-FU produced from the 5-FU prodrug is present in the patient in substantial excess over the DPD inhibitor The method is administered at a random dose.
(Item 2)
The method of claim 1, wherein the DPD inhibitor is administered at a dose of about 16-40 mg / m 2 .
(Item 3)
The method of claim 1, wherein the DPD inhibitor is administered at a dose of about 16-25 mg / m 2 .
(Item 4)
The method of item 1, wherein the 5-FU or 5-FU prodrug is administered about 11-16 hours after the DPD inhibitor is administered.
(Item 5)
The method of claim 1, wherein the 5-FU or 5-FU prodrug is administered when at least about 3-5 elimination half-life of the DPD inhibitor has elapsed since the DPD inhibitor was administered.
(Item 6)
2. The method of item 1, wherein the DPD inhibitor is administered in a dose sufficient to reduce DPD activity to less than 5% of baseline DPD activity in the patient in nerve and non-neural tissue in the patient.
(Item 7)
A dose such that the 5-FU or 5-FU prodrug is present in the patient in an amount at least a 10-fold excess of the DPD inhibitor in the administration of 5-FU produced from the 5-FU or prodrug 2. The method according to item 1, wherein the method is administered.
(Item 8)
The 5-FU prodrug is 5-fluorouridine, 5-fluorocytidine, 5-fluoro-2-deoxyuridine, 5-fluoro-2-deoxycytidine, 5′-deoxy-4 ′, 5-fluorouridine, and 5-fluoroarabinosyluracil, 5′-deoxy-5-fluorouridine, 1- (2-tetrahydrofuranyl) -5-fluorouracil, 1-C 1-8 alkylcarbamoyl-5-fluorouracil derivative, 1- (2- Tetrahydrofuryl) -5-fluorouracil, 5′-deoxy-5-fluoro-N-[(pentyloxy) carbonyl] -cytidine (capecitabine), or the group consisting of compounds converted in vivo to 5-FU, and phosphorus Item 2. The method of item 1, wherein the method is selected from its 5'-esters including acid esters.
(Item 9)
Item 2. The method according to Item 1, wherein the anticancer agent is 5-FU.
(Item 10)
Item 2. The method according to Item 1, wherein the anticancer agent is capecitabine.
(Item 11)
The method of item 1, wherein the DPD inhibitor comprises a 5-substituted uracil compound or a prodrug thereof.
(Item 12)
The DPD inhibitor, halogen atom, C 2 to 4 alkenyl group, C 2 to 4 alkenyl group substituted with a halogen, C 2 to 6 alkynyl, C 2 to 6 alkynyl group substituted with a halogen, a cyano group, C 1-4 alkyl group, or C 1 to 4 alkyl group substituted with halogen, 5-position contains uracil compound substituted method of claim 1.
(Item 13)
The DPD inhibitor is eniluracil, 5-prop-1-ynyluracil, 5-cyanouracil, 5-prop-1-ynyluracil, 5-bromoethynyluracil, 5- (1-chlorovinyl) uracil, 5-iodouracil. 5- (2-bromovinyl) uracil, (E) -5- (2-bromovinyl) uracil, 5-hex-1-ynyluracil, 5-vinyluracil, 5-trifluorouracil, 5-bromouracil and 5- (2 The method of item 1, comprising a uracil compound selected from the group consisting of -bromo-1-chlorovinyl) uracil.
(Item 14)
Item 2. The method according to Item 1, wherein the DPD inhibitor is eniluracil or a prodrug thereof.
(Item 15)
Item 2. The method according to Item 1, wherein the DPD inhibitor is eniluracil and the anticancer agent is 5-FU.
(Item 16)
Item 2. The method according to Item 1, wherein the DPD inhibitor is eniluracil and the anticancer agent is capecitabine.
(Item 17)
The DPD inhibitor is eniluracil, the anticancer agent is 5-FU, the eniluracil is administered at a dose of about 16-40 mg / m 2 , and the 5-FU is about 15 to about 16 to 16 hours later. The method of item 1, wherein the method is administered at a dose of ˜50 mg / m 2 .
(Item 18)
The DPD inhibitor is eniluracil, the anticancer agent is a 5-FU prodrug, the eniluracil is administered at a dose of about 16-40 mg / m 2 , and the 5-FU prodrug is about 11-16 The method of item 1, wherein the method is administered at a dose of about 40-150 mg / m 2 after time .
(Item 19)
19. A method according to item 18, wherein the 5-FU prodrug is capecitabine.
(Item 20)
The DPD inhibitor is eniluracil, the anticancer agent is 5-FU, the eniluracil is administered at a dose of about 16-40 mg / m 2 , and the eniluracil is administered before at least about the eniluracil. The method of item 1, wherein the 5-FU is administered at a dose of about 15-50 mg / m 2 when the 3-5 elimination half-life has elapsed .
(Item 21)
The DPD inhibitor is eniluracil, the anticancer agent is a 5-FU prodrug, the eniluracil is administered at a dose of about 16-40 mg / m 2 , and the eniluracil is administered before the eniluracil. The method of claim 1, wherein the 5-FU prodrug is administered at a dose of about 40-150 mg / m 2 when at least about 3-5 elimination half-life has elapsed .
(Item 22)
Item 22. The method according to Item 21, wherein the 5-FU prodrug is capecitabine.
(Item 23)
The DPD inhibitor is eniluracil, the anticancer agent is 5-FU, and the eniluracil reduces DPD activity in nerve and non-neural tissues in the patient to less than 5% of baseline DPD activity in the patient 2. The method of item 1 , wherein the 5-FU is administered at a dose of about 15-50 mg / m 2 about 11-16 hours thereafter .
(Item 24)
The DPD inhibitor is eniluracil, the anticancer agent is a 5-FU prodrug, and the eniluracil reduces DPD activity in nerve and non-neural tissues in the patient to less than 5% of baseline DPD activity in the patient 2. The method of item 1 , wherein the 5-FU prodrug is administered at a dose of about 40-150 mg / m 2 after about 11-16 hours .
(Item 25)
25. A method according to item 24, wherein the 5-FU prodrug is capecitabine.
(Item 26)
The DPD inhibitor is eniluracil, the anticancer agent is a 5-FU or 5-FU prodrug, and the eniluracil is administered at a dose of about 16-40 mg / m 2 , the 5-FU or 5-FU At a dose such that about 11-16 hours after the prodrug, the 5-FU or 5-FU produced from the 5-FU prodrug is present in the patient in an excess of at least 10-fold over the DPD inhibitor. The method of item 1, wherein the method is administered.
(Item 27)
A sustained release oral pharmaceutical formulation comprising a DPD inhibitor and 5-FU or a 5-FU prodrug, wherein the formulation is administered to a patient, and is at least about 11-16 hours after the DPD inhibitor is released. 5-FU or 5-FU prodrug is not substantially released and 5-FU produced from the 5-FU or prodrug after release is at least about 10 times the DPD inhibitor remaining in the patient Sustained release oral pharmaceutical formulation in excess in the patient.
Claims (46)
前記ＤＰＤ阻害剤が、神経組織と非神経組織との両方におけるＤＰＤ活性を実質的に消失させるのに十分な用量で最初に投与されることを特徴とし、ここで、前記ＤＰＤ阻害剤はエニルウラシルであり、そして前記ＤＰＤ阻害剤は、約１６〜４０ｍｇ／ｍ２の用量で投与されることを特徴とし、
前記５−ＦＵ又は５−ＦＵプロドラッグがその後に投与され、ここで、前記５−ＦＵ又は５−ＦＵプロドラッグは、前記５−ＦＵ又は前記５−ＦＵプロドラッグから生成される５−ＦＵが前記ＤＰＤ阻害剤の少なくとも５倍過剰で前記患者中に存在するような用量で、そして前記ＤＰＤ阻害剤が投与されてから前記ＤＰＤ阻害剤の少なくとも約３〜５排出半減期が経過したときに投与されることを特徴とする、組合わせ物。 A combination for minimizing neurotoxicity associated with the treatment of cancer patients comprising a DPD inhibitor and an anti-cancer agent selected from 5-FU or 5-FU prodrugs,
The DPD inhibitor is first administered to, wherein Rukoto at a dosage sufficient to substantially eliminate DPD activity in both neural tissue and non-neural tissues, wherein said DPD inhibitor eniluracil And wherein the DPD inhibitor is administered at a dose of about 16-40 mg / m 2 ,
The 5-FU or 5-FU prodrug is subsequently administered, wherein the 5-FU or 5-FU prodrug is a 5-FU or 5-FU produced from the 5-FU prodrug. Administered at a dose such that at least a 5-fold excess of the DPD inhibitor is present in the patient and when at least about 3-5 elimination half-life of the DPD inhibitor has elapsed since the administration of the DPD inhibitor A combination characterized by being made.
前記ＤＰＤ阻害剤が、神経組織と非神経組織との両方におけるＤＰＤ活性を実質的に消失させるのに十分な用量で投与されることを特徴とし、ここで、前記ＤＰＤ阻害剤はエニルウラシルであり、そして前記ＤＰＤ阻害剤は、２０〜５０ｍｇ／ｍ ２ の用量で投与されることを特徴とし、
前記５−ＦＵ又は５−ＦＵプロドラッグがその後に投与され、ここで、前記５−ＦＵ又は５−ＦＵプロドラッグは、前記５−ＦＵ又は前記５−ＦＵプロドラッグから生成される５−ＦＵが前記ＤＰＤ阻害剤の少なくとも５倍過剰で前記患者中に存在するような用量で、そして前記ＤＰＤ阻害剤が投与されてから前記ＤＰＤ阻害剤の３〜５排出半減期が経過したときに投与されることを特徴とする、組合わせ物。 A combination for minimizing neurotoxicity associated with the treatment of cancer patients comprising a DPD inhibitor and an anti-cancer agent selected from 5-FU or 5-FU prodrugs,
The DPD inhibitor is administered at a dose sufficient to substantially eliminate DPD activity in both neural and non-neural tissues, wherein the DPD inhibitor is eniluracil And the DPD inhibitor is administered at a dose of 20-50 mg / m 2 ,
The 5-FU or 5-FU prodrug is subsequently administered, wherein the 5-FU or 5-FU prodrug is a 5-FU or 5-FU produced from the 5-FU prodrug. Administered at a dose that is present in the patient in excess of at least a 5-fold excess of the DPD inhibitor and when the 3-5 elimination half-life of the DPD inhibitor has elapsed since the administration of the DPD inhibitor A combination characterized by that .
前記癌患者は、２．３ｍ The cancer patient is 2.3 m ２2 に等しいか２．３ｍEqual to or 2.3m ２2 未満の体表面積を有し、Having a body surface area of less than
前記ＤＰＤ阻害剤が、神経組織と非神経組織との両方におけるＤＰＤ活性を実質的に消失させるのに十分な用量で投与されれることを特徴とし、ここで、前記ＤＰＤ阻害剤はエニルウラシルであり、そして前記ＤＰＤ阻害剤は、４０ｍｇの用量で投与されることを特徴とし、 The DPD inhibitor is administered at a dose sufficient to substantially eliminate DPD activity in both neural and non-neural tissues, wherein the DPD inhibitor is eniluracil And the DPD inhibitor is administered at a dose of 40 mg,
前記５−ＦＵ又は５−ＦＵプロドラッグがその後に投与され、ここで、前記５−ＦＵ又は５−ＦＵプロドラッグは、前記５−ＦＵ又は前記５−ＦＵプロドラッグから生成される５−ＦＵが前記ＤＰＤ阻害剤の少なくとも５倍過剰で前記患者中に存在するような用量で、そして前記ＤＰＤ阻害剤が投与されてから前記ＤＰＤ阻害剤の３〜５排出半減期が経過したときに投与されることを特徴とする、組合わせ物。 The 5-FU or 5-FU prodrug is subsequently administered, wherein the 5-FU or 5-FU prodrug is a 5-FU or 5-FU produced from the 5-FU prodrug. Administered at a dose that is present in the patient in excess of at least a 5-fold excess of the DPD inhibitor and when the 3-5 elimination half-life of the DPD inhibitor has elapsed since the administration of the DPD inhibitor A combination characterized by that.
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| CN106692173A (en) * | 2015-11-18 | 2017-05-24 | 北京诺普德医药科技有限公司 | Anti-tumor compound composition and applications thereof |
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| JPS5687599A (en) | 1979-12-19 | 1981-07-16 | Yamasa Shoyu Co Ltd | E 55 22halogenovinyl arabinofuranosyluracil and its preparation |
| GB8629892D0 (en) | 1986-12-15 | 1987-01-28 | Wellcome Found | Antiviral compounds |
| US5157114A (en) | 1988-08-19 | 1992-10-20 | Burroughs Wellcome Co. | 2',3'-dideoxy-3'-fluoro-5-ethyngluridine |
| JP3094036B2 (en) | 1990-07-19 | 2000-10-03 | ザ ウエルカム ファウンデーション リミテッド | Enzyme deactivator |
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